Interleukin-23 (also referred to as IL-23) is a cytokine produced by dendritic cells and the like, and is a heterodimeric cytokine consisting of two subunits, i.e., a p19 subunit which is a component specific for IL-23 and the p40 subunit which is also a component of IL-12 (non-patent document 1). IL-23 binds to the IL-23 receptor (also referred to as IL- 23R) to transduce signals into cells (non-patent document 2). IL-23R is a heterodimeric receptor consisting of an IL-23R subunit and the IL-12Rβ1 subunit which is also a component of the IL-12 receptor. Also, it is known that the IL-12 receptor is a complex of an IL-12Rβ1 subunit and an IL-12Rβ1 subunit, and that IL-23 does not bind to the IL-12 receptor (non-patent document 1).
It is known that IL-23 is deeply involved in diseases, including psoriasis, inflammatory bowel disease (IBD) such as Crohn's disease (CD) or ulcerative colitis (UC), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), Behcet's disease, cancer, and ophthalmic diseases such as uveitis, dry eye, age-related macular degeneration, and ocular manifestation of Basedow's disease. Psoriasis is a chronic skin keratinization disorder and an increase in IL-23 expression in the skin of psoriasis patients has been observed (non-patent document 3).
Inflammatory bowel disease (IBD) is a chronic recurrent disease, which is represented by Crohn's disease (CD) or ulcerative colitis (UC), and causes deterioration in the function or structure of the digestive tract. It is known that lamina propria macrophages in the inflammatory sites of the intestinal tract of CD patients actively produce IL-23 (non-patent document 4), and it is considered that the lamina propria macrophages induce cytokines, including IL-21, IL-22 and IL-17, from immune cells and the like, to contribute to the inflammatory pathology of IBD (non-patent document 5).
Systemic lupus erythematosus (SLE) causes various symptoms to occur at various places over the entire body because of immune system stimulation, thus simultaneously or successively causing symptoms thought to be related to inflammation, including fever and systemic illness, as well as various symptoms which occur in joints, skin, intestinal organs, etc. It was reported that there is a positive correlation between the pathology of SLE and the number of IL-23R-positive T lymphocytes (non-patent document 6). Also, it is known that IL-23 in the blood of SLE patients is significantly higher than that in normal persons (non-patent document 7). This suggests that IL-23 is involved in SLE.
Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes lesions mainly in the vertebra and sacroiliac joints. It is known that IL-23 in the blood of AS patients is significantly higher than that in normal persons, suggesting that IL-23 is involved in the pathology of AS (non-patent document 8).
Behcet's disease is a chronic inflammatory disease characterized by inflammation of the blood vessels of varying sizes, that is, vasculitis, and it is thought that an abnormality of the immune system and the activation of neutrophils are involved in the pathology. This recurrent abnormality in blood vessels can last for several days to several months, and can reoccur several times a year. In patients with Behcet's disease, IL-23 is significantly correlated with the activity of the disease, and the stimulation of IL-23 expression is observed in the serum of patients having uveitis, whose pathology is relating to that of Behcet's disease (non-patient document 9), suggesting that IL-23 is involved in this pathology.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes deformation of joints and intense pain. IL-23 increases in the synovia and serum of RA patients (non-patient document 10), and the level of IL-23 in the serum of patients administered with a TNF blocker that is a drug for treating RA correlates with the degree of the pathology (non-patent document 11). Also, an anti-IL-23R antibody in the synovial membrane of RA patients inhibits the production of TNF-α and IL-6 (non-patent document 12), suggesting that IL-23 is involved in the pathology.
Uveitis, dry eye, age-related macular degeneration, and ocular manifestation of Basedow's disease are ophthalmic diseases in which inflammation is related. The expression of IL-23 protein or gene is increased in serum of Uveitis patient, conjunctival epithelium of dry eye patient, aqueous humor of age-related macular degeneration patient, and serum of patient affected with ocular manifestation of Basedow's disease (non-patent document 13, 14, 15, 16), suggesting that IL-23 is involved in these pathology.
Regarding cancer, IL-23 is relating to growth and progression of cancer (non-patent document 17), and in IL-23-deficient mouse with grafted cancer, the progression of the cancer is suppressed (non-patent document 18). These suggests that IL-23 is involved in the pathology.
Thus, when a monoclonal antibody that has an activity of binding specifically to the IL-23R to inhibit various actions of IL-23 can be developed, it is expected to be useful for the treatment, prevention or diagnosis of various diseases in which IL-23 is involved in disease pathology.
Antibodies that have been studied to date and which have been reported to exhibit the effect of inhibiting the function of the human IL-23R include the mouse monoclonal antibody m20D7 (patent document 1) or its humanized monoclonal antibody hum20D7 (patent document 1), the rat monoclonal antibody 8B10 (patent document 1) or its humanized monoclonal antibody (patent document 2). Among them, hum20D7 has been reviewed in the most detail, and the effect thereof on actual cell responses became clear from the results of experiments based on the inhibition of signaling of Kit 225 cells that are established cultured cells expressing the IL-23 receptor.
However, conventional antibodies do not appear to have a sufficient neutralizing activity for IL-23 signaling in cells from the viewpoint of effectiveness.
Main factors that determine the effective dosage of an antibody drug include antibody activity to inhibit ligand-receptor binding and the amount of antigen present in the body. An increase in the activity of an antibody to inhibit the binding appears to be a very beneficial improvement that leads to a decrease in the dosage of the antibody, resulting in a decrease in the financial burden or medical expenses of patients. Also, even if an antibody has a high binding activity for an antigen (a ligand, a receptor, etc.), this does not mean that the antibody can highly exhibit the desired neutralizing activity. This is because the antibody should occupy a suitable site in an antigen in order for the antibody to strongly inhibit the ligand-receptor binding. In other words, the strength of the neutralizing activity of the antibody is important when evaluating the effect of the antibody drug.
Also, the safety evaluation using animals is very important in the development of medical drugs. The international guideline ICH-S6 related to the development of medical drugs includes the following description: “Safety evaluation programs should normally include two relevant species. However, in certain justified cases one relevant species may suffice (e.g., when only one relevant species can be identified or where the biological activity of the biopharmaceutical is well understood).”. As described above, in the development of medical drugs, testing on one or more kinds of animal species other than humans is required; however, in order to carry out a test on animal species when developing an antibody drug, the antibody is required to have cross-reactivity with antigens derived from animal species other than humans. However, it is generally not easy to obtain a monoclonal antibody that has high selectivity and maintains high activity while displaying species cross-reactivity.
Therefore, obtaining a anti-human IL-23 receptor antibody which has strong neutralizing activity compared to conventional antibodies and shows species cross-reactivity is required for use in the treatment, prevention or diagnosis of various diseases by administering the antibody to humans.